Astellas and Amgen join the pan-KRAS push

Astellas’s first attempt at KRAS degradation, with the G12D-specific ASP3082, looked lacklustre, but the company isn’t stopping its efforts here: it has just taken a pan-KRAS degrader, ASP5834, into the clinic, a new clinicaltrials.gov listing shows.

While ASP5834 is the only pan-KRAS degrader in development, according to OncologyPipeline, Amgen has a new entrant in a more crowded area; namely pan-KRAS inhibition. Also among the new listings is a tissue factor ADC from Exelixis, representing the latest attempt to diversify away from Cabometyx, and another AstraZeneca project designed to harness CD8+ (rather than CD4+) T cells.

Degrader determination

Astellas reported data at last year’s ESMO with its KRAS G12D degrader ASP3082, showing ORRs of 19% and 23% in pancreatic cancer and NSCLC respectively. However, results were largely seen as disappointing in the context of dose-limiting toxicities. And further doubt was heaped on ASP3082 by the development of another Astellas G12D degrader, ASP4396, which uses a different enzyme for degradation.

However, ASP3082 is still in play, with Astellas recently claiming that it had achieved proof-of-concept in pancreatic cancer and NSCLC.

The new pan-KRAS degrader, ASP5834, will therefore need to show differentiation, although Astellas appears to have a head start in this arena.

Not so Amgen, which was the first company to get a KRAS G12C inhibitor approved in Lumakras, but looks well behind in the pan-KRAS race. AMG 410 joins Revolution Medicines’ daraxonrasib, which leads the pack, as well as more recent entrants from the likes of Pfizer, Lilly and BridgeBio. 

Like BridgeBio’s BBO-11818, AMG 410 is said to inhibit both the on and off states of KRAS, and Amgen has claimed a wider therapeutic index than other KRAS inhibitors. Now the group needs to prove that this makes a difference in the clinic.

Tissue factor & guided IL-2

Targeting tissue factor has yielded an approved ADC in the form of Pfizer and Genmab’s Tivdak, and others are taking aim at this target, most recently Adcendo, via a deal with Multitude Therapeutics.

Now Exelixis has taken its tissue factor-targeting ADC, XB371, into the clinic. The group hopes to find replacements for its blockbuster Cabometyx, although one of these efforts, the tyrosine kinase inhibitor zanzalintinib, has had some recent misses, as well as hits.

Cytokines have had an even more torrid history, and AstraZeneca will be hoping to succeed with AZD6750 in a field where many others have failed. Astra’s project is novel in that it’s described as a CD8-guided IL-2 agent, although it’s unclear how this might enhance activity. Others have attempted to improve IL-2 selectivity by avoiding the alpha IL-2 receptor subunit, but to no avail.

Astra is also developing multispecific MAbs designed to recruit CD8-positive, rather than CD4-positive T cells; both are harnessed by conventional T-cell engagers.

Meanwhile Miltenyi, best known for selling the Clinimacs cell manufacturing instrument, also has its own pipeline, which includes the now clinical-stage MB-CART 2219.1. This is far from the only CD19 x CD22 Car in development, but it might be set apart if it uses the private company’s fast manufacturing process, which came under the spotlight at last year’s ASH meeting during a presentation on the CD19 x CD20-targeting zamtocabtagene autoleucel.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 30 Jul and 14 Aug 2025.